Field of the Invention
The disclosure relates to a cell culture control system, a cell culture control method, and a non-transitory computer readable storage medium.
Priority is claimed on Japanese Patent Application No. 2014-103719, filed May 19, 2014, the contents of which are incorporated herein by reference.
Description of Related Art
A production of a biological medicine, which uses high molecular biological molecule, includes a culture process and a purification process. In the culture process, objective substances are produced by biological response. In the purification process, foreign substances which are produced in the culture process are removed, and a purity of the objective substances is improved. In the culture process of an antibody medicine which represents the biological medicine, animal cells such as CHO cells are mainly used. However, the animal cells are easily affected by a culture environment. For the reason, in a case where the culture environment is not kept appropriately, a quantity and a quality of the objective products are affected.
In comparison with a chemical medicine, the production of the biological medicine is easily affected by a process, and it is difficult to produce the biological medicine stably. Therefore, developing a production technology for implementing an efficient and stable production is desired strongly.
Causes for degradation of the culture environment are such as mechanical stress by agitation and gas flow, depletion of nutrient and oxygen, accumulation of waste material such as lactic acid and ammonia produced by the cells. For the reason, a production method, which controls basic environmental factors such as dissolved oxygen concentration, pH, temperature, and agitation speed of a culture fluid, and supplies materials which the cells require while culturing, is used. The supplied materials are such as nutrient components included in the culture fluid and augmenting agents for improving growth rate or production rate of the cells.
A culture method for supplying materials while culturing is such as a continuous culture, a perfusion culture, and a fed-batch culture. In the continuous culture and the perfusion culture, the culture environment can be easily kept constant, and stable production can be conducted. However, there is a risk that a contamination remains after the contamination is generated, and there is a disadvantage of high cost caused by large consumption of the culture fluid.
On the other hand, in the fed-batch culture, although a culture fluid for feeding (feed agent) is added into a tank, the culture fluid for feeding is not removed from the tank. The fed-batch culture is a culture method for densifying the cells by attenuating the waste material such as lactic acid and ammonia which are harmful for the cells. Also, the fed-batch culture is a majority culture method in a current commercial production. For example, the fed-batch culture is described in Japanese Unexamined Patent Application Publication No. 2003-235544, Japanese Unexamined Patent Application Publication No. 2008-178344, and Danny Chee Furng Wong, et al., Biotechnology and Bioengineering, VOL. 89, NO. 2, Jan. 20, 2005: 164-177.
In the Japanese Unexamined Patent Application Publication No. 2003-235544, a culture method for calculating factors such as a specific growth rate and a specific production rate which are important for culturing the cells is described. The factors are calculated from online monitoring values (for example, pH and temperature) and analysis values obtained by sampling a cell concentration and cell metabolism components. The cells are cultured while monitoring a predicted value and an actual value of them.
In the Japanese Unexamined Patent Application Publication No. 2008-178344, a culture method for calculating a variation amount of a living cell number and a reduction amount of culture medium components. Components which are included in the culture fluid are added in accordance with a relation between the variation amount of a living cell and the reduction amount of culture medium components, and the components which are included in the culture fluid are kept constant.
In the Japanese Unexamined Patent Application Publication No. 2003-235544 and the Japanese Unexamined Patent Application Publication No. 2008-178344, the culture methods for culturing the cells while keeping the culture environment in a suitable condition are described. However, there is a need for the both methods to analyze the culture fluid by sampling.
In Danny Chee Furng Wong, et al., Biotechnology and Bioengineering, VOL. 89, NO. 2, Jan. 20, 2005: 164-177, an advantageous effect such as a production rate improvement caused by a nutrient source low concentration control is described. Also, it is described that variations of their concentration affect a glycosylation pattern which relates to antibody quality.
However, in the analysis of the components, which is necessary for the cell culture methods described in the Japanese Unexamined Patent Application Publication No. 2003-235544 and the Japanese Unexamined Patent Application Publication No. 2008-178344, about one hour is required, the contamination risk is increased, and there is a limitation of man-hour. For the reason, the analysis is generally performed once daily. Therefore, the culture condition (for example, the concentration of the each component) cannot be monitored at short intervals.
When the cells are cultured, for example, it is difficult to control to keep “substrate concentration” constant. Therefore, it is difficult to keep the concentration range (about ±0.1 mM) described in Danny Chee Furng Wong, et al., Biotechnology and Bioengineering, VOL. 89, NO. 2, Jan. 20, 2005: 164-177.